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46,XX/46,XY is a chimeric genetic disorder caused by having two distinct cell populations within the body. The chimerism arises in utero from the combination of an XX zygote and an XY zygote (which otherwise would have developed into twins) into a single embryo. It is not to be confused with mosaicism and hybridism. 46,XX/46,XY is typically associated with intersex conditions such as ambiguous genitalia and hermaphroditism.

46,XX/46,XY chimerism can be identified during pregnancy by prenatal screening or in early childhood through genetic testing and direct observation. Identifying the condition early on is important for shaping the individual’s gender identity.

Physical
Physical symptoms vary widely from individual to individual. Symptoms range from ambiguous genitalia to true hermaphroditism to normal genitalia. Due to the variation, genetic testing is the only way to reliably make a diagnosis.

46,XX/46,XY is possible if there is direct observation of one or more of the following: As individuals with 46,XX/46,XY possess both ovarian tissue and testicular tissue, depending on the individual, gonads (ovaries or testes) may function fully, partly or not at all.
 * 1) Small phallus midway in size between a clitoris and a penis
 * 2) Incompletely closed urogenital opening (shallow vagina)
 * 3) Abnormal urethra opening on the perineum

At puberty, a mix of male and female characteristics may emerge. Some individuals will experience deepening of the voice and secondary hair development, while others may experience breast tissue development.

Segmentation of skin (distinct patches of skin) has also been observed. However, this trait is not unique to 46,XX/46,XY chimerism. It has also been observed in other types of chimerism.

Cognitive
Individuals afflicted with the condition do not experience cognitive impairment.

Genetic Mechanism
46,XX/46,XY is an example of tetragametic chimerism because it requires four gametes – two sperm and two ova.
 * 46,XX/46,XY is most commonly explained by the in utero combination of two fertilized zygotes. Two ova from the mother are fertilized by two sperm from the father. One sperm contains an X chromosome; the other contains a Y chromosome. The result is that a zygote with an XY genotype and a zygote with an XX genotype are produced. Under normal circumstances, the two resulting zygotes would have gone on to become fraternal twins. However, in 46,XX/46,XY, the two zygotes fuse shortly following fertilization to become a two-cell zygote made up of two different nuclei. The zygotes fuse early enough that there is no risk of them developing into conjoined twins. Variations of this mechanism include fertilization of an ovum and its first or second polar body by two sperm.


 * 46,XX/46,XY can also be explained by a mosaic-based mechanism. A single zygote is formed from the fertilization of a normal X ovum by an aneuploid XY sperm. The resulting XXY zygote divides to give three cell lines: 46,XX/46,XY/47,XXY. The aneuploid 47,XXY cell line is eliminated during early embryogenesis. The 46,XX/46,XY cell lines remain and go on to become a chimeric individual.
 * 46,XX/46,XY can also arise when a haploid ovum undergoes a round of mitosis, and the subsequent daughter cells are fertilized by an X and a Y sperm, respectively.

Diagnosis
Diagnosing a chimera is particularly difficult due to the random distribution of 46,XX and 46,XY cells within the body. An organ might be made up of a mix of 46,XX and 46,XY, but it may also be made up entirely of one genotype only. When that is the case, no abnormalities are noted and other types of tissues need to be analyzed.

Pre-birth Testing

 * 1) Ultrasound - looking for ambiguous genitalia
 * 2) Amniocentesis - looking for a karyotype of 46,XX/46,XY
 * 3) Cord blood sampling - looking for a karyotype of 46,XX/46,XY

Post-birth Testing

 * 1) Blood testing - looking for red blood cells of different blood types
 * 2) Tissue sampling - looking for more than one set of DNA within the sample